Luteinizing Hormone Releasing Hormone (LHRH) is secreted by the hypothalamus and carried to the pituitary gland where it stimulates secretion of follicle stimulating hormone and luteinizing hormone which, in turn, stimulate ovarian follicle development, the conversion of ovarian follicle to corpus luteum, tubule development in the testicles, and production of progesterone and testosterone. Thus, release of LHRH from the hypothalamus causes ovulation and the formation of corpus luteum in females and causes spermatogenesis in males.
LHRH is a decapeptide having the following structure: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2, wherein, according to convention, the amino group of each amino acid appears to the left and the carboxyl to the right with the hydroxyl of the carboxyl of the terminal Gly being replaced by an NH.sub.2 group. The conventional abbreviations for the amino acids are: Glu (glutamic acid), pGlu (pyroglutamic acid), His (histidine), Trp (tryptophan), Ser (serine), Tyr (tyrosine), Gly (glycine), Leu (leucine), Arg (arginine), Pro (proline), Lys (lysine) and Cys (cysteine). Except for glycine which has no optical center, all amino acids are of the L-configuration unless otherwise indicated. LHRH may be produced as described in U.S. Pat. Nos. 4,159,980 and 4,213,895.
U.S. Pat. Nos. 3,880,825; 3,941,763; 4,034,082; 4,072,668; 4,075,192; 4,143,133; 4,143,136; 4,211,769; 4,234,571; and 4,263,282 disclose analogs of LHRH which act as agonists or antagonists of LHRH. U.S. Pat. No. 4,010,261 discloses administering LHRH analogs to an animal in amounts such as 2-200 micrograms per kilogram of body weight to effect the reproductive cycle.
LHRH and its several analogs have been studied as potential agents for fertility control. Free LHRH or its agonists, when administered frequently and in comparatively high doses, exhibit antifertility effect. (Contraception, 24:647-655 (1981) and Fertility Sterility, 38:190-193 (1982). Also, repeated administration of potent antagonist may be used for antifertility effect. LHRH and its agonists work by pituitary desensitization, whereas the antagonists act by competitive inhibition. Antifertility and other antigonadotropic effects of high doses of LHRH and its agonists or the antagonist analogs are immediate but of short duration, requiring frequent administration. Thus they are not of practical use for veterinary or wildlife use as such. In addition, in some cases, large amounts of the analogs may cause unwanted and adverse side effects.
LHRH or its appropriate analogs conjugated to carrier proteins can also be administered to an animal as an antigen to induce the formation of host antibodies to LHRH; the antibodies will subsequently act against the body's own LHRH. Thus, a long term antigonadic effect is established. Using LHRH or various LHRH analogs as antigens is described in the literature: Arimura et al., Endocrinology, 93:1092-1103(1973); Fraser et al., Journal of Endocrinoloqy, 63:399-406 (1974); Jeffcoate et al., Immunochemistry, Vol. 11, p. 75-77 (1974); Clarke et al., Journal of Endocrinology, 78:39-47 (1978); Johnson et al., Animal Science, 66:719-726 (1988); Falvo et al., Animal Science, 63:986-994 (1986); Pique et al., Immunochemistry, Vol. 15, p. 55-60 (1978); Stevens et al., American Journal of Reproductive Immunology, 1:307-314 (1981); and in U.S. Pat. No. 3,963,691. U.S. Pat. No. 4,608,251 discloses LHRH analogs useful for stimulating anti-LHRH antibodies and the vaccines using such analogs.
LHRH or its analogs are usually administered via a vaccine after conjugation to immunogenic carriers to a mammal to stimulate the immune system to produce anti-LHRH antibodies which react with LHRH to effectively reduce its concentration in the body. The effects caused by the presence of LHRH are thus reduced or eliminated, including ovulation and formation of corpus luteum in females and spermatogenesis in males. The anti-LHRH antibodies induced by LHRH or its analogs thus effectively prevent conception by reducing the amount of LHRH in the body.
This technique is, however, not totally effective in preventing conception for an initial period of variable length following injection. The production of antibodies in sufficient amounts to reduce the LHRH concentration to a level that can prevent conception generally takes about 4-6 weeks or more. During that lag period, unwanted conception may occur. A method is, therefore, needed which can prevent conception during the lag period as well as prevent conception during metabolic life of the induced antibodies. Such a method is needed to prevent conception in cases of unwanted pregnancies, particularly for domestic/stray pets and wild animals.
At present there are 43 million dogs and 31 million cats in the United States and their numbers increase daily. Stray dogs and cats along with wild animals such as skunks and raccoons are known to be major sources of rabies transmission to domestic animals and humans. Surgical removal of reproductive organs, e.g., spaying and castration, is presently a commonly used method for preventing reproduction in such animals. However, surgery is relatively costly, time consuming and impractical when used with wild or stray animals. Prevention of the explosive population increase of wild animals, including deer and horses in park and forest preserves, requires a practical and acceptable method of birth control for wild and free ranging animals.